Adhesive for percutaneous absorption, adhesive composition for percutaneous absorption and preparation for percutaneous absorption

ABSTRACT

To offer adhesives for percutaneous absorption, adhesive compositions for percutaneous absorption and preparations for percutaneous absorption which show high ability to dissolve drugs and to dissolve absorption promoting agents and enable high percutaneous absorption and have suitable cohesion and adhesion and do not damage the skin when detached. 
     Adhesives for percutaneous absorption which comprise a copolymer in which the constituents are methoxyethyl acrylate 40-60 wt %, lauryl(meth)acrylate 30-40 wt % and a polar monomer 10-25 wt % only.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to adhesives for percutaneous absorptionadhesive compositions for percutaneous absorption and preparations forpercutaneous absorption, used in order to administer a drug through theskin continuously over along period.

(2) Description of the Related Art

In recent years various preparations such as patches and tapes forexternal use attached to the surface of the skin have been developed aspreparations for percutaneous absorption in order to administer drugsthrough the surface of the skin. In this kind of adhesive preparation,the role of the adhesive is extremely important and the adhesive isrequired to adhere to the skin, to permit stable sustained drug releaseand to show little irritation to the skin. In order for thesepreparations for percutaneous absorption to show these characteristics,an adhesive which permits stable drug release over a long period (3 daysto a week) after attachment is important.

However, the adhesives for preparations for percutaneous absorptionproposed in the prior art cannot considered suitable for long termcontinuous drug administration.

For example, JP2-203048 A proposes an adhesive for external use whichuses a copolymer which is a copolymer formed from an alkyl ester ofacrylic acid or methacrylic acid at 40-80 wt %, an ethylenic unsaturatedmonomer containing a hydroxyl group at 10-50 wt % and an ethylenicunsaturated monomer containing a carboxyl group at 1-10 wt %, which hasa glass transition temperature. (Tg) of 250K or less and a gel contentafter drying of 25 wt % or more. This adhesive for medical use has thedisadvantage that the content in the copolymer of ethylenic unsaturatedmonomers having an alkoxy group is low, and therefore the saturationsolubility of drugs and absorption promoters is low.

JP4-150865 A proposes an adhesive which includes a crosslinked copolymerof 99-99.9 wt % of a mixture of an acrylic acid alkyl ester andalkoxyalkyl acrylate in which the proportion of the alkoxyalkyl ester ofacrylic acid at 50 wt % or less, together with a monomer containing acarboxyl group and/or hydroxyl group at 0.1-1 wt %. This adhesive isbased on a (meth)acrylic acid ester, and like JP 2-232048 A above it hasthe drawback that the saturation solubility of drugs and absorptionpromoters is low.

JP 4-272754 A discloses adhesives for medical use which include morethan 50% of a monomer derived from an alkoxyalkyl ester of acrylic acidwhich gives a homopolymer with a Tg of −35° C.; however, in thisinvention. Methoxyethyl acrylate is positively excluded as beingunsuitable. Moreover, as the comparison examples presented below willshow drugs and absorption promoters have a plasticizing effect on theseadhesives, and they have the drawback that the cohesion of the adhesivecomposition is lowered and there are considerable adhesive residues lefton the skin.

Since impregnation of drugs into the adhesive at high concentration andlong-term sustained high release are important in the development ofpreparations for percutaneous absorption, various techniques have beenproposed with the object of long-term sustained high drug release. Forexample, JP 5-246752 A proposes adhesives for percutaneous absorptioncomprising a mixture of an acrylate adhesive or silicone adhesive andPoly(Vinylpyrrolidone) as adhesives allowing the stable presence ofdrugs in the supersaturated state without crystallization. However, thistechnique is proposed in order to maintain a thermodynamically unstablestate of supersaturation for a long time, and there is a considerablerisk of recrystallization of the drug, limiting the efficacy thereof.Similarly; JP 6-75600 A proposes preparations for percutaneousabsorption impregnated with tulobuterol in the dissolved state and thecrystalline state. These preparations also have the drawback that inmany cases, crystallization of the drug causes lowered adhesion of theadhesive preparation.

SUMMARY OF THE INVENTION

The object of the present invention is to offer adhesives forpercutaneous absorption, adhesive compositions for percutaneousabsorption and preparations for percutaneous absorption wherein drugshave high solubility and long-term release properties, and which have asuitable adhesive force and cohesive force, without causing damage tothe skin when detached.

The present inventors have perfected the present invention as the resultof concerted studies on optimum adhesives for continuous long-termadministration of drugs, with the discovery that this object is met byadhesives for percutaneous absorption comprising a copolymer theconstituents of which are methoxyethyl acrylate 40-60 wt %,lauryl(meth)acrylate 30-40 wt % and a polar monomer 10-25 wt % only withoutstanding properties such as skin adhesion and drug release and lowskin irritation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. A graph of the results of evaluation of ketoprofen percutaneousabsorption using rat skin.

FIG. 2. A graph of the results of evaluation of felbinac percutaneousabsorption using rat skin.

DETAILED DESCRIPTION OF THE INVENTION

Adhesives for percutaneous absorption according to Claim 1 arecharacterized in as much as they comprise a copolymer in which theconstituents are methoxyethyl acrylate 40-60 wt %, lauryl(meth)acrylate30-40 wt % and a polar monomer 10-25 wt % only. The aforementionedadhesives for percutaneous absorption achieve high drug solubility byusing as a monomer methoxyethyl acrylate, which is highly hydrophilic.Adhesives based on other commercially available alkoxyalkyl acrylateshave been investigated, but only methoxyethyl acrylate is useful. Forexample, butoxyethyl acrylate has comparatively low cohesive strength initself, and when a drug is dissolved at high concentration in anadhesive based on said monomer, or when an absorption promoter is added,it becomes plastic and cohesion is extremely decreased, so that it isnot practically useful as a preparation for percutaneous absorption.

In the present invention, the proportion of methoxyethyl acrylate in thecopolymer is 40-60 wt %, and preferably 45-55 wt %. When the proportionis greater than 60 wt %, gelling occurs during copolymerization and itbecomes insoluble, and the viscosity of the resulting copolymer is poor.Similarly, with less than 40 wt %, the high drug solubility ofmethoxymethyl acrylate cannot be expressed, which is unsatisfactory forthe object of the present invention.

Lauryl(meth)acrylate, which is the second monomer constituent of theaforementioned constituent of the copolymer in the present invention,needs to present at 30-40 wt %. Lauryl(meth)acrylate raises the adhesionof the adhesives according to the present invention, and also conferssuitable hydrophobic characteristics on the adhesive; therefore, whencombined with the principal monomer it provides suitable conditions fordissolving a wide range of drugs and absorption promoters differing inpolarity.

When the proportion of lauryl(meth)acrylate in the aforementionedcopolymer is 40 wt % or more, the copolymer becomes strongly hydrophobicand drug solubility is lowered. Similarly, when it is 30 wt % or lessthe object of conferring suitable hydrophobicity on the adhesive isinadequately achieved.

Use of 2-ethylhexyl(meth)acrylate—shorter than lauryl(meth)acrylate—asthe second monomer is unsatisfactory because the capacity to dissolvehydrophobic drugs and absorption promoters (e.g. ibuprofen and isopropylmyristate) is low; and use of stearyl acrylate, with a longer alkylchain, as the second, monomer is also unsatisfactory, because theadhesion of the copolymer is poor.

The third monomer in the copolymer in the present invention needs to bea polar monomer at 10-25 wt %. The reason for the presence thereof isthat these give higher cohesion without damaging other properties, andalso because they bring about crosslinking of the adhesive.

The aforementioned polar monomer is included at 10-25 wt % because lessthan 10 wt % is unlikely to give higher cohesion, and with more than 25%wt % the polarity of the adhesive becomes too high and the adhesiveproperty is decreased, and it is impossible to obtain suitable adhesion.When the range is 10-25 wt % there is a good balance of cohesion andadhesion.

Examples of aforementioned polar monomers include acrylic acid,methacrylic acid, acrylamide, N-vinyl-2-pyrrolidone,N,N-dimethylacrylamide, 2-hydroxyethyl acrylate, and vinyl acetate, andthese can be used singly or in combination.

The adhesives for percutaneous absorption described in Claim 2 arecharacterized in that the aforementioned polar monomer is one or moreselected from a set comprising N-vinyl-2-pyrrolidone, acrylic acid and2-hydroxyethyl acrylate; the adhesives for percutaneous absorptiondescribed in Claim 1 are characterized in that N-vinyl-2-pyrrolidone isan essential constituent of the aforementioned polar monomer. Inaddition, the adhesives for percutaneous absorption described in Claim 3are characterized in that the content of N-vinyl-2-pyrrolidone is 5 wt %or more in the aforementioned copolymer. With such a constitution, thecohesion of the adhesive is suitably high, and the balance of cohesionand adhesion is good for an adhesive for percutaneous absorption.

The adhesive compositions for percutaneous absorption described in Claim4 are characterized in that a drug or an added value product which is askin cosmetic is incorporated in an adhesive for percutaneous absorptiondescribed in any of Claims 1-3.

Examples of aforementioned drugs include antipyretic and antiphlogisticdrugs such as ketoprofen and piroxicam, skeletal muscle relaxants,anti-Parkinsonian drugs, antihistamines, angina, drugs for arrhythmias,antihypertensive drugs, hormones and vitamins. As the quantity of addeddrug, 0.05-30 wt % in the adhesive composition for percutaneousabsorption is ideal in order to obtain satisfactory adhesion, cohesionand efficacy.

Examples of cosmetic added value products include whitening constituentssuch as ascorbyl-palmitate and oil-soluble liquorice root extract,anti-wrinkle constituents such as retinyl acetate and retinyl palmitate,constituents such as vitamin E and capsacin for promoting blood flow,and vitamins such as vitamin D₂, vitamin D₃ and vitamin K.

Adhesive compositions for percutaneous absorption described in Claim 5are characterized in that a promoter of percutaneous absorption isfurther added.

Examples of aforementioned absorption promoters include fatty acidesters such as isopropyl palmitate and isopropyl myristate, glycerolesters such as glyceryl monolaurate and glyceryl monooleate, acid amidessuch as lauric acid diethanolamide, and neutral surfactants such aspoly(ethylene glycol)dilauryl ether. These absorption promoters do notenhance the effect on percutaneous absorption if the quantity added istoo small, and lower adhesion when the quantity is too great, and areideally added at 3-40 parts by weight to 100 parts by weight of theaforementioned copolymer.

The adhesive compositions for percutaneous absorption described in Claim6 are characterized in that the aforementioned promoter of percutaneousabsorption is isopropyl myristate.

The adhesive compositions for percutaneous absorption described in Claim7 are characterized in that the aforementioned adhesive composition forpercutaneous absorption is crosslinked by a crosslinking agent.

The aforementioned crosslinking agent is added with the object ofraising the cohesion of the adhesive, and examples include isocyanatesand metal chelates: the quantity added is ideally 0.1-2 parts by weightto 100 parts by weight of the aforementioned copolymer. With less than0.1 parts by weight crosslinking is weak and does not confer anyimprovement in cohesion; and with more than 2 parts by weight, adhesionis weakened.

The preparations for percutaneous absorption described in Claim 8 arecharacterized in that an adhesive ointment comprising adhesivecomposition for percutaneous absorption described in any of Claims 4-7is formed on at least one side of a support.

The copolymer employed in the present invention can be obtained, forexample, by free radical polymerization using 1-3 aforementionedmonomers. As the polymerization processes, solution polymerization,emulsion polymerization or suspension polymerization can be employed.Solution polymerization is particularly ideal because the molecularweight distribution is comparatively narrow and there is littlevariation in adhesion.

In order to produce a preparation for percutaneous absorption of thepresent invention, an aforementioned drug or cosmetic value-addedproduct, an absorption promoter and/or crosslinking agent, for example,can be added to an adhesive solution comprising an aforementionedcopolymer and then laminated onto a detachable paper by applicationusing a method such as a knife coater or roll coater, and then dried inan oven at a temperature of 50-100° C. for 1-10 minutes to attach anaforementioned adhesive composition to the support.

The thickness after drying of the adhesive layer so applied to thesupport is preferably 30-120 μm. When it is less than 30 μm the adhesionof the adhesive is weak, and when it is greater than 120 μm it isdifficult to coat and dry the adhesive.

The aforementioned support can take the form of a woven fabric, nonwovenfabric, porous film or moulded film, ideally 10-100 μm thick. Wovenfabric, nonwoven fabric or porous films are ideal in that they allowgood passage of water vapor, whereas moulded films are good forproviding a barrier to bacteria and for waterproofing.

The present invention will next be described by citing practicalexamples thereof; however, the present invention is not restricted tothese. Except where otherwise specified, “parts” in the embodiments andcomparison examples below refers to parts by weight.

EMBODIMENTS 1-3 AND COMPARISON EXAMPLES 1-8

200 g of ethyl acetate as a polymerization solvent, 0.05 g ofazobisbutyronitrile as an initiator and the monomers shown in Table 1below (grams) were loaded into a reaction vessel and the reaction vesselwas purged with nitrogen, followed by polymerization for 15 hours at 70°C. The resulting copolymer solution was coated with a knife coater ontoa poly(ethylene terephthalate) film to give a thickness of the dryadhesive layer of 100 μm, and then dried at a temperature of 90° C. for15 minutes to produce adhesive sheets.

The resulting adhesive sheets were attached to the keratin layer of theshaven skin of the abdomen of Wistar rats, and detached after 24 hours,and adhesion and the state of the adhesive layer were observed with thenaked eye. The results obtained are presented in Table 1.

TABLE 1 Monomer weight (g) Adhesion Cohesion Embodi- MEA/DA/NVP/AA/HEANo detachment No adhesive left ment 1 (43/38/6/3/10) during 24 h on thebody Embodi- MEA/DA/NVP/AA No detachment No adhesive left ment 2(48/34/15/3) During 24 h on the body Embodi- MEA/DA/NVP/HEA Nodetachment No adhesive left ment 3 (50/35/5/10) during 24 h on the bodyCompar- BEA/DA/NVP/AA/HEA No detachment No adhesive left ison 1(43/38/6/3/10) during 24 h on the body Compar- BEA/DA/NVP/AA Nodetachment No adhesive left ison 2 (48/34/15/3) during 24 h on the bodyCompar- MEA/DA/NVP/HEA No detachment No adhesive left ison 3(35/60/5/10) during 24 h on the body Compar- MEA/DA/NVP/AA/HEA Nodetachment No adhesive left ison 4 (35/50/3/2/10) during 24 h on thebody Compar- MEA/DA/NVP/AA Detached after — ison 5 (48/24/25/3) 1 hCompar- MEA/EHA/NVP/HEA No detachment No adhesive left ison 6(50/35/5/10) during 24 h on the body Compar- MEA/SA/NVP/AA/HEA Detachedafter — ison 7 (43/38/6/3/10) 2 h Compar- MEA/DA/NVP/AA No detachment Noadhesive left ison 8 (50/45/3/2) during 24 h on the body MEA:Methoxyethyl acrylate DA: Lauryl acrylate NVP: N-vinyl 2-pyrollidone AA:Acrylic acid HEA: Hydroxyethyl acrylate BEA: Butoxyethyl acrylate EHA:2-Ethylhexyl acrylate SA: Stearyl acrylate —: Not tested

EMBODIMENTS 4-6 AND COMPARISON EXAMPLES 9-16

Adhesive sheets were produced as in Embodiment 1, except that 20 partsof isopropyl myristate were added to 100 parts of the copolymer, andevaluated in the same way. The results obtained are presented in Table2.

TABLE 2 Monomers, weight (g) Adhesion Cohesion Embodi- MEA/DA/NVP/AA/HEANo detachment No adhesive left ment 4 (43/38/6/3/10) during 24 h on thebody Embodi- MEA/DA/NVP/AA No detachment No adhesive left ment 5(48/34/15/3) during 24 h on the body Embodi- MEA/DA/NVP/HEA Nodetachment No adhesive left ment 6 (50/35/5/10) during 24 h on the bodyCompar- BEA/DA/NVP/AA/HEA No detachment Adhesive left ison 9(43/38/6/3/10) during 24 h on the body Compar- BEA/DA/NVP/AA Nodetachment Adhesive left ison 10 (48/34/15/3) during 24 h on the bodyCompar- MEA/DA/NVP/HEA No detachment Adhesive left ison 11 (35/60/5/10)during 24 h on the body Compar- MEA/DA/NVP/AA/HEA No detachment Noadhesive left ison 12 (35/50/3/2/10) during 24 h on the body Compar-MEA/DA/NVP/AA No detachment Adhesive left ison 13 (48/24/25/3) during 24h on the body Compar- MEA/EHA/NVP/HEA Detached — ison 14 (50/35/5/10)after 1 h Compar- MEA/SA/NVP/AA/HEA No detachment Adhesive left ison 15(43/38/6/3/10) during 24 h on the body Compar- MEA/DA/NVP/AA Nodetachment Adhesive left ison 16 (50/45/3/2) during 24 h on the bodyMEA: Methoxyethyl acrylate DA: Lauryl acrylate NVP: N-vinyl2-pyrollidone AA: Acrylic acid HEA: Hydroxyethyl acrylate BEA:Butoxyethyl acrylate ERA: 2-Ethylhexyl acrylate SA: Stearyl acrylate —:Not tested

EMBODIMENTS 7-9

Adhesive sheets were produced as in Embodiment 1, except that 40 partsof isopropylmyristate and 0.5 part of an isocyanate crosslinking agent(Nippon Polyurethane Co., Coronate L) were added to 100 parts of thecopolymer, and evaluated in the same way. The results obtained arepresented in Table 3.

TABLE 3 Monomers, Weight (g) Adhesion Cohesion Embody- MEA/DA/NVP/AA/HEANo detachment No adhesive left ment 7 (43/38/6/3/10) during 24 h on thebody Embody- MEA/DA/NVP/AA No detachment No adhesive left ment 8(48/34/15/3) during 24 h on the body Embody- MEA/DA/NVP/HEA Nodetachment No adhesive left ment 9 (50/35/5/10) during 24 h on the bodyMEA: methoxyethyl acrylate DA: Lauryl acrylate NVP: N-vinylpyrrolidoneAA: acrylic acid HEA: hydroxyethyl acrylate

EMBODIMENTS 10-12 AND COMPARISON EXAMPLE 17-22

The copolymers obtained in embodiments (1-3) and comparison examples(1-4, 6 and 8) were used in testing for drug solubility in adhesivescomprising different copolymers, using felbinac as the drug.

Felbinac was added to each of the copolymer solutions to give 2, 4 or8%, made into a rolled sheet and the solvent was removed by heating at90° C. for 10 minutes. The resulting adhesives containing the drug werestored at room temperature for 4 weeks, and the presence or absence ofcrystals was observed.

The results are presented in Table 4.

TABLE 4 Examples Adhesive Felbinac (%) Comparison used 2 4 8 Nature ofthe drug-containing sheet Embodyment 10 Embodyment 1 ◯ ◯ ◯ Good adhesionand cohesion Embodyment 11 Embodyment 2 ◯ ◯ ◯ Good adhesion and cohesionEmbodyment 12 Embodyment 3 ◯ ◯ ◯ Good adhesion and cohesion Comparison17 Comparison 1 ◯ X X Poor cohesion. Adhesive of 4, 8% felbicac sheetleft on the skin Comparison 18 Comparison 2 ◯ X X Poor cohesion.Adhesive of 4, 8% felbicac sheet left on the skin Comparison 19Comparison 3 ◯ X X Poor cohesion. Adhesive of 4, 8% felbicac sheet lefton the skin Comparison 20 Comparison 4 ◯ X X Good adhesion and cohesionComparison 21 Comparison 6 ◯ ◯ ◯ Poor cohesion. Adhesive of 8% felbicacsheet left on the skin Comparison 22 Comparison 8 ◯ X X Poor cohesion.Adhesive of 4, 8% felbicac sheet left on the skin ◯: No crystals X:crystals

EMBODIMENTS 13-15 AND COMPARISON EXAMPLES 23-27 In Vitro Evaluation ofPercutaneous Absorption of Ketoprofen and Felbinac

(Preparation of Samples for In Vitro Testing of Percutaneous Absorption)

The drugs were dissolved in adhesive compositions by adding isopropylmyristate as an absorption promoter to copolymer solutions to give 20parts per 100 parts of the adhesive constituent, to give a saturatedconcentration in the adhesive compositions. The drugs used wereketoprofen and felbinac. The compositions containing the dissolved drugswere coated onto poly(ethylene therephthalate) film to give a thicknesswhen dry of 100 μm, and dried at a temperature of 90° C. for 15 minutes,to produce drug-containing adhesive sheets. The composition of thesamples used in the in vitro tests is presented in Table 5.

TABLE 5 Fel- Adhesive binac Nature of the drug- used (%) containingsheet Example/ Comparison Embodyment 13 Embodyment 1 25 Good adhesionand cohesion Embodyment 14 Embodyment 2 22 Good adhesion and cohesionComparison 23 Comparison 3 6 Poor cohesion Comparison 24 Comparison 4 8Poor cohesion Comparison 25 Comparison 6 25 IPM bleeding, poor adhesionComparison 26 Comparison 8 8 Poor cohesion Embodyment / ComparisonEmbodyment 15 Embodyment 1 6.8 Good adhesion and cohesion Embodyment 16Embodyment 2 7.0 Good adhesion and cohesion Comparison 27 Comparison 41.2 Good adhesion and cohesion (In vitro absorption tests)

Tests of permeation of rat skin were performed using the samples inTable 5 above. The tests were performed using Franz diffusion cellshaving a diffusion cross-sectional area of 3.14 cm² were used. As thepermeation membrane, shaved abdominal skin from male Wistar rats wasused, and physiological saline+polyethylene glycol 600 (80:20 v/v) wasused as the receptor solution. The sample was attached to the keratinlayer of the rat skin and at set times thereafter 100 ml of receptorsolution was sampled, and the concentration of drug permeated throughrat skin into the receptor solution was confirmed by usinghigh-performance liquid chromatography (HPLC).

(HPLC Conditions)

Column: ODS reverse-phase partition column

Mobile phase: Ketoprofen—phosphate buffer (pH 3.0)+acetonitrile (50:50vol/vol)

-   -   Felbinac—ditto

Detection: Ketbprofen—UV 250 nm

-   -   Felbinac—ditto

(Results of the In Vitro Absorption Tests)

The results obtained are presented in FIG. 1 (ketoprofen) and FIG. 2(felbinac).

Comparing the embodiments and comparison examples, it is evident thatexcept for Comparison Example 25, the embodiments showed persistentpercutaneous absorption for 36 hours, whereas in the case of thecomparison examples absorption was virtually complete after 8 hours.This indicates that the high drug solubility shown of the copolymeradhesives shown in the embodiments results in the possibility of highrelease over a long period.

Comparison Example 26 showed persistent drug release over a long periodbut poor adhesion, precluding practical use as a preparation forpercutaneous absorption.

When an adhesive for percutaneous absorption of a composition of thepresent invention, drugs can be impregnated into the adhesive at highconcentration, making it possible to give long-term persistentpercutaneous absorption and good adhesion.

1. An adhesive for percutaneous absorption comprising a copolymer inwhich the constituents are methoxyethyl acrylate 40-60 wt %,lauryl(meth)acrylate 30-40 wt %, and a polar monomer 10-25 wt % only,wherein said polar monomer comprises N-vinyl-2-Pyrrolidone.
 2. Theadhesive for percutaneous absorption as described in claim 1, whereinsaid polar monomer further comprises one or more selected from a setcomprising acrylic acid and 2-hydroxyethyl acrylate.
 3. The adhesive forpercutaneous absorption as described in claim 1, whereinN-vinyl-2-Pyrrolidone is in an amount of 5 wt % or more in saidcopolymer.
 4. An adhesive composition for percutaneous absorptioncomprising a drug or a value-added cosmetic substance for the skin inthe adhesive for percutaneous absorption described in any one of claims1, 2 and
 3. 5. The adhesive composition for percutaneous absorption asdescribed in claim 4, further comprising a promoter of percutaneousabsorption.
 6. The adhesive composition for percutaneous absorption asdescribed in claim 5, wherein said promoter of percutaneous absorptionis isopropyl myristate.
 7. The adhesive composition for percutaneousabsorption as described in claims 4, which is crosslinked by acrosslinking agent.
 8. A preparation for percutaneous absorptionproduced by forming an adhesive ointment comprising the adhesivecomposition for percutaneous absorption described in claims 4 on atleast one side of a support.